Boronic esters and acids are widely used cross coupling reagents in medicinal and biological fields. Boronic acid based cross coupling reactions are often present in the synthesis of pharmaceuticals, agrochemical compounds, and natural products. More recent advances in cross coupling involving boronic acids include copper(II) mediated oxygen and nitrogen arylation, as well as coupling between alkenes, alkynes, carbonyl compounds, and imines. The syntheses of chiral homoallylic alcohols and amines have also been achieved through catalytic asymmetric allylboration using allylboronate esters.
Boronic acids have wide application in organic synthesis and especially in the formation of C—C bonds through the Suzuki-Miyaura cross coupling reaction. This cross coupling reaction has become ubiquitous in the construction of asymmetric biaryl systems. Because of the value of the boronic acid starting materials, great effort has been put forward to find new and more efficient methods of synthesis. Major advancements in application and versatility of the Suzuki coupling continue to increase the demand for new methods of synthesizing boronic acids and esters.
A well established method for producing arylboronic acids is the Brown-Cole transmetallation of aryllithium reagents with an excess of trialkylborate, such as trimethyl-, triethyl-, or triisopropylborate, followed by acid hydrolysis. Due to the high reactivity of lithium reagents, the reaction must be carried out at −78° C. to avoid multiple additions. Several catalytic methods have also been developed for synthesizing arylboronic acids using transition metals, such as palladium, rhodium, ruthenium, and iridium. Arylboronic esters have also been prepared through metal catalyzed C—H activation. These routes to boronic acids are widely used in industry because of their functional group tolerance. The challenges associated with these methods are the high cost of the catalytic components, catalyst decomposition, regioselectivity and non-trivial isolation of the products free of heavy metal impurities.
Several other methods for synthesizing boronic esters and acids have been developed including the Miyarua-Masuda reaction, where arylboronate esters are obtained by palladium (Pd)-catalyzed borylation of aryl halides with dialkoxyboranes or tetraalkoxydiboron reagents. These Pd catalyzed methods are tolerable to a wide range of functional groups which allows for wide application in the pharmaceutical industry. Additionally, borylation via rhodium (Rh)-catalyzed C—H activation has been developed. The drawbacks of these methods include the invariable requirement of excess boron reagent, high cost associated with the catalysts, catalyst decomposition, and the isolation of products free of heavy metal impurities.
In comparison, Grignard reagents have found limited use in the synthesis of boronic acids. Direct reaction of Grignard reagents with trialkylborates invariably gives a mixture of products arising from multiple additions. This problem could be circumvented by using excess amounts of trialkylborate. Even so, mild, low-cost synthetic processes to produce boronic acids or boronic esters are desirable.
Dunach et al. have reported synthesis of aryl and benzyl boronate esters by reacting an aryl or benzyl halide with Mg0, followed by reaction with pinacolborane (WO2010/055245). However, the substrate scope was limited to aryl and benzyl groups, and the reported examples utilized stoichiometric amounts of base (e.g., triethylamine) under refluxing conditions in tetrahydrofuran for 15 h. Therefore, there remains a need for efficient reactions under mild conditions with expanded substrate scope to produce boronic esters and boronic acids.